PROJECT SUMMARY/ABSTRACT The unique effects of comorbid cannabis and nicotine and tobacco product (NTP) use on neuromaturational brain changes is unknown despite preclinical evidence of a functional interaction between delta-9- tetrahydrocannabinol (THC) and nicotine in the brain that may enhance susceptibility to the development of problematic substance use patterns and addiction severity symptoms. As cannabis becomes more accepted and accessible and nicotine delivery methods more advanced and widespread among youth, the neurobiological effects of co-use of these two substances during adolescence must be better understood. Adolescents who use both cannabis and NTPs may be at unique risk for neural and cognitive changes that increase vulnerability for future substance-related problems. The primary objective of the proposed research is to recruit a sample of adolescents (N=100) ages 16-22 who report concurrent and simultaneous cannabis and NTP co-use, cannabis only, NTP use only, and minimal to no use of either substance to compare differences in: (1) structural and vascular brain integrity, (2) neurocognition, and (3) substance-related problems (e.g., negative affect, craving). The study will use cutting- edge magnetic resonance imaging techniques (restriction spectrum imaging and pseudo-continuous arterial spin labeling), cognitive testing, and detailed mental health assessment for a precise understanding of the unique and combined effects of cannabis and NTP use on white matter and gray matter integrity, cerebral blood flow, cognitive control and impulsivity, and addiction severity symptoms. Adolescents are one of our most vulnerable populations (e.g., high peak use rates, high vulnerability for addiction, high susceptibility to peer use attitudes and perceptions), and as a result are specifically targeted by the tobacco industry. These individuals may be similarly vulnerable to cannabis use, particularly if the regulatory environment continues to become increasingly permissive. Yet, there is a remarkable paucity of research examining co-use of these two substances on neural health and neurocognitive functioning in youth. The proposed research will lead to a greater understanding of the unique and combined effects of these commonly used substances on brain development and risk for substance use disorders, which will guide neuroscience-informed prevention and intervention programs, public health messages, and public policy.